WO2004011899A2 - Procede et appareil d'acquisition de spectre multidimensionnel par un balayage unique - Google Patents

Procede et appareil d'acquisition de spectre multidimensionnel par un balayage unique Download PDF

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WO2004011899A2
WO2004011899A2 PCT/US2003/021314 US0321314W WO2004011899A2 WO 2004011899 A2 WO2004011899 A2 WO 2004011899A2 US 0321314 W US0321314 W US 0321314W WO 2004011899 A2 WO2004011899 A2 WO 2004011899A2
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sample
series
single scan
subensembles
pulses
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PCT/US2003/021314
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WO2004011899A3 (fr
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Lucio Frydman
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Yeda Research And Development Co. Ltd.
Fleit, Lois
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Priority to EP03771578.6A priority Critical patent/EP1529227B1/fr
Priority to AU2003247923A priority patent/AU2003247923A1/en
Priority to IL16641703A priority patent/IL166417A0/xx
Priority to US10/728,069 priority patent/US6873153B2/en
Publication of WO2004011899A2 publication Critical patent/WO2004011899A2/fr
Publication of WO2004011899A3 publication Critical patent/WO2004011899A3/fr
Priority to US11/056,131 priority patent/US7271588B2/en
Priority to IL220203A priority patent/IL220203A/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/46—NMR spectroscopy
    • G01R33/4633—Sequences for multi-dimensional NMR
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/483—NMR imaging systems with selection of signals or spectra from particular regions of the volume, e.g. in vivo spectroscopy
    • G01R33/4833—NMR imaging systems with selection of signals or spectra from particular regions of the volume, e.g. in vivo spectroscopy using spatially selective excitation of the volume of interest, e.g. selecting non-orthogonal or inclined slices

Definitions

  • the present invention relates to a method and apparatus for acquiring multidimensional spectra within a single scan, and more particularly, to a method and apparatus for acquiring multidimensional nuclear magnetic resonance spectra within a single scan.
  • the present invention also relates to a variety of methods employing the principles of these methods or techniques.
  • spectroscopy studies include optical, paramagnetic, electron, mass and nuclear magnetic resonance (NMR) spectroscopies. Included among this latter category is the method known as magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • the object of the present invention is to provide a method and apparatus for acquiring multidimensional spectra, and especially multidimensional nuclear magnetic resonance spectra, within a single scan.
  • This is accomplished by a novel method and apparatus that enables treating a sample to acquire multidimensional spectra within a single scan comprising the steps of: (1) partitioning, at least notionally, a sample into a set of independent subensembles endowed with different resonance frequencies; (2) implementing a polychromatic irradiation of the sample whereby the various subensembles are selectively manipulated by a time-incremented series of excitation or refocusing sequences; (3) follow these various selective manipulation processes by a homogeneous sequence capable of generating an observable spectral signal from each of the subensembles; (4) simultaneously monitoring the observable signals arising from the various subensembles in a resolved fashion; and (5) processing the set of signals acquiring in this manner into a complete multidimensional spectral data set.
  • the acquisition of the multidimensional spectra can result from the practice of any type
  • the object of the present invention is to provide a method and apparatus for acquiring multidimensional spectra, and especially multidimensional nuclear magnetic resonance spectra, within a single scan.
  • this is accomplished by a novel method and apparatus that enables the acquisition of multidimensional NMR spectra within a single continuous scan.
  • the invention can, in turn, shorten the acquisition time of any multidimensional application or experiment by several orders of magnitude.
  • the new invention is compatible with the majority of multidimensional NMR pulse sequences hitherto proposed, and can be implemented using known magnetic resonance hardware.
  • a method and apparatus for treating a sample to acquire multidimensional magnetic resonance spectra within a single scan comprising the steps of: (1 ) applying a magnetic field gradient on the sample so as to endow spins at different positions within the sample with different resonance frequencies; (2) applying a train of frequency-incremented radiofrequency (RF) pulses in unison with this gradient (or with an oscillating version of thereof), so as to endow spins at different positions within the sample with incremented values of their evolution times, thus creating an effective spatial encoding of the spins' frequencies (3) applying if needed a homogeneous mixing pulse sequence at the conclusion of the various spatial encoding processes, capable of creating a set of observable spin signals; (4) capturing the signals thus created from the sample while decoding the spins' spatial locations using a second set of acquisition magnetic field gradient; (5) subjecting the collected data to a suitable rearrangement and Fourier analysis procedure so as to retrieve the final spectrum being sought.
  • RF radiofrequency
  • Lying at the core of this new invention is the application of a magnetic field gradient, operated in unison with a train of spatially-selective radiofrequency (RF) pulses.
  • RF radiofrequency
  • this unwinding step can be immediately reversed, and then, repeated multiple (N 2 ) times by alternating the sign of the acquisition gradient, thereby allowing monitoring of the ⁇ 2 frequencies of the spins active during the second, directly-detected t 2 period.
  • Signals obtained during such cyclic rephasing/dephasing train can be arranged into a bidimensional data set, which by Fourier analysis along t 2 will lead to a desired 2D NMR spectrum correlating ⁇ 1 and ⁇ 2 frequencies.
  • the subordinate methods of the present invention include i. The novel method of the analysis by multidimensional NMR of rapidly- changing dynamic systems.
  • the present invention enables the routine application of complex multidimensional NMR experiments to such hyperpolarized systems, enabling extensions of chemical studies.
  • iii The novel method for the characterization of analytes subject to flow through a NMR spectrometer, and thereby the coupling of multidimensional NMR with high-throughput chromatographic techniques.
  • the combination of NMR with chromatographic techniques opens one of the most promising routes to the characterization of chemical and biochemical samples.
  • the residence time of such flowing samples through the NMR reception coil is very limited ( «1 sec). Therefore only unidimensional NMR spectra have been so far collected in real time on this kind of samples.
  • the method of the present invention will enable the acquisition of multidimensional NMR spectra on samples being chromatographed, thereby providing a new and much more powerful way to characterize plant extracts, natural products, amino acids, peptides, nucleic acids and other types of chemicals being separated in a chromatographic column.
  • the novel method for rapid survey of large numbers of chemicals like those made nowadays available by Combinatorial Chemistry.
  • Combinatorial Chemistry is a novel approach to the synthesis of organic, inorganic and pharmacological molecules, whereby thousands of compounds are synthesized and tested in a variety of ways for chemical and/or biological activity.
  • Combinatorial methods have provided much of the impetus for the ongoing revolution currently undergoing in Proteomics and Metabonomics.
  • the invention described herein allows the incorporation of ultrafast multidimensional NMR methods to this array of high-throughput techniques, thereby providing a new route to the discovery of new catalysts, new pharmaceuticals, pharmaceutically- active peptides and nucleic acids, etc.
  • the present invention enables the speeding up of such multidimensional NMR quantum computers by several orders of magnitude.
  • the new ultrafast multidimensional MRI method of the present invention that results can be employed to monitor brain metabolism, pulsating regions (thorax, abdomen), etc. It can also aid for the real-time positioning of malignancies and hence as aid in surgical procedures.
  • the novel method of the present invention enables other kinds of multidimensional spectroscopies to be reduced to a single-scan acquisition.
  • Figures 1 A-B present graphically and pictorially steps of the invention as they relate to the underlying the acquisition of 2D NMR spectra within a single scan.
  • Figures 2A-B present graphically and pictorially the steps of the invention as they relate to carrying out the selective excitation step in the initial stage of Figure 1 , without encoding excitation artifacts, by means of a gradient-echo refocusing.
  • Figures 3A-C present graphically and pictorially the steps of the invention as they relate to the acquisition while in the presence of an oscillating gradient; positioning of data points in the (k/v ⁇ t ⁇ -space; and further repositioning of the collected data points in preparation for a fast Fourier transform processing.
  • Figure 4 is a simplified pictorial diagram describing the origin of peaks along the indirect dimensions of ultrafast NMR experiments.
  • Figures 5A-G show graphically and pictorially the data acquisition and processing stages involved in the retrieval of ultrafast NMR experiments on a chemical sample.
  • Figures 6A-D compare graphically and pictorially the similar results afforded by conventional vis- ⁇ -vis ultrafast 2D 1 H- 1 H COSY and TOCSY NMR on a chemical sample.
  • Figures 7A-D are similar to Figure 6, but for cases involving two different kinds of heteronuclear 2D correlations: (A) with direct detection; (B) with indirect detection.
  • Figures 8A-B illustrate the inventive method's capability to the implementation of constant-time 2D NMR experiments, using simple pulse sequences as examples.
  • Figures 9A-E illustrate the applicability of the inventive method to the acquisition of 2D NMR images (pure 2D MRI).
  • Figure 10 illustrates conceptually the invention as shown in Figure 1 regarding the application of the invention concerning the ultrafast acquisition of 3D NMR spectra.
  • Figures 12A-B shows the present invention as applied to the acquisition of arbitrary ⁇ /-dimensional NMR spectra (A), and illustrates that according to the invention a single-scan 4D NMR experiment can be completed within 94 ms (B).
  • Figure 13 is a block diagram of a preferred embodiment of the apparatus of the present invention with respect to NMR/MRI.
  • Figure 14 is a flow chart illustrating the inventive method as it is applied towards the acquisition of multidimensional NMR spectra.
  • a 2D spectrum l(v l 7 v 2 ) can be obtained if this approach is followed to collect a two-dimensional signal S as a function of t ⁇ and t2, and subsequently Fourier transformed. Yet the signals that are actually generated by the nuclear spin ensemble can only be directly detected as a function of -2 > and hence the spins' coherent evolution as a function of the remaining time variable cannot be monitored directly. According to the invention, the remaining time variable is monitored indirectly in a unique manner.
  • this partitioning of the sample offers the potential to collect the complete bidimensional data set within a single scan. This of course, depends on techniques for endowing the various ⁇ / sub-ensembles with individual tf evolution times, and then for monitoring the signals that these generate independently and within a single transient.
  • Figures 1A and 1B show graphically and pictorially the method of the present invention and more particularly, depict a simplified scheme or method respecting the application of spatially-heterogeneous excitation and detection schemes, toward the acquisition of multidimensional NMR data within a single scan.
  • the excitation that triggers the initial spin evolution is assumed to affect spins in different positions within the sample at a series of incremented times (Figure 1A).
  • Figure 1A This creates a spatial encoding of the initial ti evolution period, which is then monitored as a function of -2 via the spatially-resolved acquisition of the NMR signal.
  • this strategy allows one to retrieve a complete 2D NMR spectrum within a single scan ( Figure 1 B).
  • the train of frequency-shifted pulses needs to be applied in combination with a synchronized reversal in the sign of the field gradient (gradient echoes) if an evolution that is solely dictated by the internal spin evolution frequencies is to be achieved. Assuming that gradients in this pair are applied for equal time lengths Tp (e.g., the RF pulse duration), this will result in a gradient echo where any dephasing that may have affected hitherto excited magnetizations becomes compensated.
  • Tp e.g., the RF pulse duration
  • Figures 3A, 3B and 3C illustrate the protocol employed in order to achieve the spatially-resolved data acquisition stage that is required by the method or scheme as given in Figure 1A.
  • Dots symbolize the data points digitized during the course of positive and negative acquisition gradients.
  • This oscillatory gradient module is then repeated ⁇ t ⁇ times, with N2 defining the number of effective points along f ⁇ .
  • the open and closed dots symbolize the coordinates of such points.
  • the simplest route to achieve an inhomogeneous set of evolution times is by imposing an auxiliary gradient on top of the homogeneous external magnetic field B 0 .
  • This in turn enables a sequential excitation of the spins, based on the use of a train of frequency-shifted selective RF pulses ( Figure 2A).
  • Using a gradient-based step or scheme requires imparting on successively-excited spin packets an evolution phase that reflects solely the internal coupling frequencies, but not the frequencies defined by the artificial gradient.
  • This step or goal is achieved by the invention by following the action of each selective pulse with reversal of the +Ge gradient employed to implement the spatially-heterogeneous excitation via an opposite gradient of amplitude -G e ( Figure 2B). Assuming that gradients in this pair are applied for equal time lengths Tp (e.g., the RF pulse duration), this will result in a gradient echo where any dephasing that may have affected hitherto excited magnetizations becomes compensated.
  • Tp e.g., the RF pulse duration
  • the next aim is to monitor the signals originating from these individually- excited slices, after they have been subject to the mixing process step.
  • This spatially- resolved detection of the signal as a function of -2 amounts to a hybrid spectroscopic/imaging experiment, an acquisition that can be implemented within a single scan using a number of alternatives, see for example, P. T. Callaghan, "Principles of Nuclear Magnetic Resonance Microscopy” Oxford University Press, Oxford, 1991, and B. Blumich, "NMR Imaging of Materials” Oxford University Press, Oxford, 2000.
  • the collection of NMR signals while subject to an alternating field gradient was adopted towards this end, see for example P. Mansfield, Magn.
  • Figure 4 is a simplified pictorial diagram describing the origin of peaks along the indirect dimensions of ultrafast NMR experiments.
  • the heterogeneous nature of the ti evolution leads to an encoding of the internal precession frequency ⁇ along the z axis (second panel from left); this spiral of spin-packets is subsequently unwound by an acquisition gradient Ga possessing an identical z spatial dependence.
  • the coherent addition of spin-packets thus leads to a sharp echo along the k coordinate whose position reveals the extent of ⁇ i encoding prior to the mixing process — in essence, the spectrum along the indirect dimension.
  • Figure 4 A graphical depiction of this aspect or feature is illustrated in Figure 4, which analyzes the fate of magnetizations throughout a portion of an ultrafast acquisition assuming a simplified "five-slices" sample.
  • the initial excitation segment of the sequence affects successively the various slices and imposes on them a spatial encoding; yet this encoding will only reflect the initial ⁇ 1 internal evolution frequency, since the effects of the auxiliary Ge are being compensated by reliance on gradient echoes.
  • the extent of the ensuing evolution can therefore be described for a particular site by a "winding" of its magnetization through the sample, with a pitch dictated by exp[iC ⁇ (z-zo)].
  • This spatial winding is then preserved as either a phase- or an amplitude-modulation throughout the mixing period, with the result that the overall signal available for detection at the beginning of the acquisition will in general be null.
  • a gradient is applied on the sample, whose spatial e ⁇ p[i ⁇ a ⁇ G a (t')dt'z] dependence is capable of o unwinding the initial spiral of magnetizations.
  • Figures 5A to 5G illustrate and show graphically and pictorially the summary of events involved in the single-scan acquisition of phase-sensitive 2D NMR spectra, illustrated with 1 H data recorded on a solution of n-butylchloride dissolved in CDCI3 and utilizing a 2D NMR sequence devoid from actual mixing process.
  • time-domain data is collected using the spatially-selective excitation/detection procedures illustrated in Figures 2B and 3A.
  • the magnified inset shows the signal (magnitude) arising from an individual Ta period, depicting in essence the compound's unidimensional ni spectrum.
  • Figure 5C a 2D contour plot of the unidimensional data set illustrated in Figure 5B, following a rearrangement of its 2NkN2 points according to their k and -2 coordinates according to the procedure given in Figure 3B. Interleaved data sets acquired with +G a and -Ga gradients are still present at this point, thus resulting in a mirror-imaging of the signal along the k- axis.
  • Figures 5D and 5E show pairs of data sets resulting upon separating the interleaved +G a l-G a arrays in (C) into two (k,t2) signals possessing NkN ⁇ points each, as illustrated in the process leading from Figure 3B to Figure 3C.
  • Figures 5A to 5 G illustrates a basic 2D *H NMR acquisition on an r.-butylchloride sample, using a 2D test pulse sequence (Figure 5A) that actually involves no mixing process or step as an example of the data processing required by the methodology of the present invention.
  • Identical frequencies have here been active throughout the evolution and acquisition times, and only diagonal peaks result.
  • Figure 5B This is a reflection of the method's built-in capability to FT the signal that was encoded during ti, via the G a gradient defining the /c-axis.
  • FIG. 5A to 5G The 2D NMR data in Figures 5A to 5G arise from a sequence deprived of a real mixing process, and hence its peaks are arranged solely along the main homonuclear diagonal.
  • Figures 6A to 6D compare graphically and pictorially between single-scan (Figure 6A and 6B) and conventional ( Figures 6C and 6D) 2D phased data sets acquired on an n-butylchloride/CDCl3 sample. Schematics of the COSY and TOCSY sequences utilized in these experiments are shown on the left- and right-hand side panels, respectively. The structure of the molecule, indicating its proton sites' shifts (in ppm), is also shown on top for ease of analysis.
  • FIG. 6 illustrates the contrast between conventional and ultrafast 2D NMR spectra for the model compound when subject to two "real" 2D NMR sequences: COSY, correlation spectroscopy, which correlates cross-peaks among directly coupled neighbors, and TOCSY, total correlation spectroscopy, which establishes cross peaks among the full system of mutually- coupled spins, see for example R. R. Ernst, G. Bodenhausen and A. Wokaun, "Principles of Nuclear Magnetic Resonance in One and Two Dimensions" Clarendon, Oxford, 1987, and H. Kessler, M. Gehrke and C. Griesinger, Angew. Chem. Int. Ed. Engl. 27, 490 (1988).
  • both normal and fast acquisition schemes convey an identical spectral information, though in radically different amounts of experimental time.
  • the spatial encoding principles illustrated so far for monitoring 2D homonuclear connectivities can also be employed for implementing heteronuclear correlations.
  • Application of the invention in this respect or such experiments will rely on applying the ⁇ ⁇ /-driven spatial winding of magnetizations on a particular spin species S, preserving this encoding as an amplitude modulation during a mixing which implements a heteronuclear S- / transfer, and then decoding this information during the acquisition by gradients applied on the second / species.
  • Figures 7A, 7B, 7C and 7D show examples where 2D correlations are established between different kind of nuclei.
  • Figures 7A and 7B show a 2D 1 H- 13 C single-scan NMR spectrum obtained on a pyridine/CDCl3 sample using the directly- detected heteronuclear correlation sequence sketched on top, which involves a spatial encoding of the " ⁇ magnetization and subsequent decoding on the ⁇ C channel.
  • the total acquisition time was in this case ⁇ 200 ms; other details are as in Figure 6.
  • Figure 7 illustrates how two sequences that form the basis of several directly- and indirectly-detected heteronuclear correlation experiments, see for example R. R. Ernst, G. Bodenhausen and A. Wokaun, "Principles of Nuclear Magnetic Resonance in One and Two Dimensions” Clarendon, Oxford, 1987; H. Kessler, M. Schorke and C. Griesinger, Angew. Chem. Int. Ed. Engl. 27, 490 (1988); J. Cavanagh, W. J. Fairbrother, A. G. Palmer III and N. J. Skelton, "Protein NMR Spectroscopy: Principles and Practice” Academic Press, San Diego, 1996; and M.
  • a common NMR approach to encode indirect evolution frequencies relies on systematically varying the location of a 180° pulse through the duration of a constant evolution period ⁇ , see for example Ernst et al and Kessler et al cited above.
  • Such pulse will refocus the linear evolution terms (chemical shifts and heteronuclear couplings) yet leave homonuclear couplings unaffected, thus providing an appealing option to achieve homonuclear decoupling.
  • the spatial encoding scheme introduced according to this invention can also be incorporated into this so-called constant-time modality, as illustrated by the example shown in Figures 8A and 8B.
  • Figure 8A shows a mixing-less pulse sequence, showing the three nonequivalent proton sites in the molecule aligned along the main diagonal.
  • Figure 8B is idem but incorporating a 50 ms long isotropic mixing period, leading to cross peaks among all mutually coupled protons (right).
  • 2D NMR experiments or applications are those underlying the acquisition of 2D magnetic resonance imaging (MRI).
  • 2D MRI is, arguably, the most widely executed kind of NMR experiment, see for example M. A. Brown and R. C. Semelka, "MRI: Basic Principles and Applications” New York, 1999, yet from a spectroscopic standpoint it is actually a particular case of the much wider world of 2D NMR, see for example Ernst et al cited above.
  • the main difference between conventional 2D NMR and 2D MRI applications or experiments is that whereas in the former the interactions to be correlated are purely internal, for instance couplings or shifts, the latter tends to neglect these for the sake of monitoring an artificial interaction given by the application of an external gradient in the magnetic field.
  • Field gradients are also integral constituents of the spin evolution periods of the ultrafast scheme in Figures 1A and 1B, yet particular care is taken in this sequence to remove their effects via systematic changes in their sign and the ensuing generation of gradient echoes devoid of imaging information. If, however, these gradients oscillations were to be removed, the same acquisition scheme would become useful for the ultrafast acquisition of 2D MRI sequences.
  • Figures 9A to 9E show the adaptation and exemplification of how the new inventive method can be employed to collect 2D NMR images (pure 2D MRI) within a single scan.
  • Figure 9A shows the modifications implemented on the basic spectroscopy scheme given in Figure 5A, whereby the position of the spins becomes encoded by removing the gradient echo refocusing from the excitation process.
  • Figure 9B shows a pulse sequence resulting upon taking the G e "off' period in Figure 9A to zero; the consequence is a continuous, highly efficient RF pulse whose offset varies linearly between O ⁇ and ONI- Figures 9C and 9D show 2D 1 H MRI images obtained using the pulse sequences illustrated in Figures 9A and 9B, and reflecting as contour plots the water location profile used in the phantom that was experimentally tested (shown in the center for the sake of comparison), see Figure 9E.
  • Figure 9A illustrates the basic single-scan 2D MRI experiment that would result from implementing these changes, with ⁇ i becoming now associated with a position-dependent frequency G 1 r 1 and ⁇ 2 encoding a position-dependent frequency G 2 r 2 (with r and r 2 reflecting any pair of x, y or z orthogonal directions). Furthermore, as no need for waiting for a refocusing -Ge delay is now needed after each initial RF excitation pulse, the possibility arises of employing a continuous, windowless train of variable-frequency RF pulses over the course of ti.
  • Figure 9B presents the pulse sequence resulting when taking this concept to the limit of very short pulse widths; a single chirp pulse where frequency offsets are continuously swept between Of and ONI then results, capable of carrying out the spins' excitation in a very efficient and robust manner.
  • either of these schemes is capable of affording 2D MRI images in a single, ultrafast scan.
  • the abilities of this scheme are comparable to those of echo-planar imaging (EPI), a fundamental MRI tool that is also capable of affording 2D images within a single scan, see for example P. Mansfield, J. Phys. C: Solid State Phys. 10, 55 (1977), and M. K. Stehling, R. Turner and P.
  • EPI echo-planar imaging
  • the present description has focused so far on the use of spatial encoding methods and protocols to accelerate the acquisition of various 2D NMR experiments.
  • the invention employs the same principles for acquiring higher-dimensional NMR spectra within a single scan, a particularly important goal given the exponential increase that the duration of /V-dimensional NMR experiments exhibit with respect to N.
  • a relevant point to notice in order to proceed with the extension of the new ultrafast acquisition invention to higher dimensionalities, are the dissimilar roles that the gradient's strength and the gradient's geometry play in the collection of the data.
  • the strengths Ge, Ga will define important range and resolution characteristics of the single-scan 2D NMR spectrum.
  • the actual geometrical distribution of the gradient by contrast, is mostly responsible for relatively minor line shape characteristics related to the sharpness of the echo formation.
  • This equation represents a winding of spin-packets, arranged this time along the gradient's ⁇ t m geometry and possessing non-uniform A(x,y,z) weights. Such winding will once again lead to an overall zero magnetization when considering an ⁇ chemical shift evolution and integration over the whole sample.
  • this will again allow one to map the evolution frequencies that had been active prior to the mixing process in the form of a constructive interference among individual spin-packets.
  • this spatial helix of spin-packets can be wound and unwound numerous times by periodically reversing the Y,m acquisition gradient, in a process that will encode the spin frequencies as a function of -2 and thereby enable the collection of 2D NMR spectra within a single scan.
  • the actual shapes of the resulting /(-echoes — shapes which will in turn define the kind of peaks observed in ultrafast experiments along the indirect domain — will depend on the sample's and gradient's spatial dependencies.
  • the echo positions on the other hand will be independent of these details, and solely reflect a site's given ⁇ - shift.
  • numerical simulations reveal a behavior that overall is uniform, with minor line shape differences that can be rationalized in terms of the characteristics assumed for the gradients and the sample.
  • a train of frequency-shifted pulses is first applied to achieve the spatial encoding of spins throughout different axial positions in the sample (-7); this is followed by a second rf-driven encoding of the spin evolution during -2 along a linearly independent radial direction.
  • Data are finally collected while in the presence of oscillating acquisition gradients, which decode the initial ⁇ 7, ⁇ 2 frequencies along the (kz,k ⁇ ) axes while monitoring the spin evolution along a third (-3) time axis.
  • the actual direction (or even linearity) of the gradients used in the encoding is not fundamental.
  • Such scheme incorporates two separate gradients arranged along linearly independent geometries, which implement two consecutive spatial encodings of the spin evolution.
  • Each one of these encoding processes assumed here for simplicity to lie along the x and z directions, proceeds independently and along an outline similar to the one described previously for the single-axis 2D NMR method or experiment.
  • the first of these gradients will thus induce an ⁇ ⁇ -dependent winding of the spin-packets along the z direction, while for each one of these z slices the second gradient will generate an ⁇ -dependent encoding along the x axis.
  • the digitized signal can then be regarded as a function of three independent variables: k z ⁇ J G z (t)dt ; k x x J G x (t)dt ; and a time -3 associated with the final free evolution frequency ⁇ 3.
  • k z -C z 0. 1
  • Figures 11A to 11 D demonstrate the inventive method illustrated and described with reference to Figure 10.
  • Figure 11A shows a TOCSY-HSQC pulse sequence assayed to corroborate the possibility of collecting a 3D NMR spectrum within a single scan.
  • Figure 11 B depicts an iso-surface representation of the full 3D NMR spectrum acquired on a glyceroI/D2 ⁇ sample, using the pulse sequence indicated in Figure 11 A. The total time required to carry out this experiment was ca. 141 ms.
  • Figures 11 C and 11 D illustrate 2D contours resulting from projecting the 3D NMR data against the remaining spectral axis, and illustrate the expected line shapes for the compound.
  • Figures 11 A to 11 D gives experimental proof on the feasibility of implementing single-scan 3D NMR, utilizing a 1 H- 13 C- 1 H TOCSY-HSQC experiment on a glycerol/D2 ⁇ sample, see as example J. Cavanagh, W. J. Fairbrother, A. G. Palmer III and N. J. Skelton, "Protein NMR Spectroscopy: Principles and Practice” Academic Press, San Diego, 1996.
  • the method of the invention can be adapted and can be extended to an arbitrary number of dimensions.
  • the principles underlying the invention as explained in detail above, can be generalized to an arbitrary number of dimensions. Such generalization is made possible by the countless gradient geometries that can, in principle, be utilized for encoding the spin evolution, represented for instance by the spherical harmonic set ⁇ Yi t rr ⁇ discussed earlier. When applied in combination with a train of frequency selective RF pulses, any of these eigen functions can be employed to wind an independent spiral of spin-packets, of the type summarized by the Fourier relation in eq. (9).
  • Figures 12A and 12B show the present invention applied to the acquisition of arbitrary ⁇ /-dimensional NMR spectra.
  • the method step is shown, of the present invention, for the acquisition of arbitrary /V-dimensional NMR spectra, and involving N-1 independent spatial encoding events prior to the last mixing event, and their simultaneous decoding during the course of the signal acquisition.
  • Figures 12A and 12B Illustrate the method of the present invention with respect to the acquisition of a 4D NMR technique or experiment within a single scan, that can be completed within 94 ms.
  • FIG. 12A and 12B summarizes the kind of method or scheme that would then be involved in these arbitrary /V-dimensional experiments; the graph in Figure 12B illustrates experimental 4D NMR results collected on the practice of the disclosed method on the basis of such principles, with the triple-axes spatial encoding required by such sequence implemented with the aid of x, y, z spectroscopy gradients applied in combination with a constant-time protocol. Collecting similar spectra using conventional means might have taken several hours, perhaps even days, of continuous spectrometer use.
  • the present invention also contemplates a method for the analysis or monitoring by multidimensional NMR of rapidly changing dynamic systems.
  • the method of the present invention can enable monitoring in real time, a variety of chemical and physical processes and reactions that are hitherto outside the capabilities of NMR. These include the realtime monitoring of ongoing chemical reactions, and the folding of biological macromolecules, as described in C. M. Dobson and P. J. Hore, Nat. Struct. Biol. 5, 504 (1998).
  • this is accomplished by a method for the real-time monitoring of a chemical or physical process comprising the steps of: (1 ) conducting a chemical or physical process in real-time; (2) monitoring the on-going chemical or physical process in real time by repeatedly acquiring multidimensional nuclear magnetic resonance spectra within a single scan at preselected short time intervals; each single scan being carried out comprising the steps of the methods described herein previously in detail.
  • the single scan can be carried out by: (3) partitioning a predetermined sample of the on-going chemical or physical process into a set of independent subensembles; (4) applying the single scan to the sample by exciting the set of subensembles by a time-incremented series of selective excitation sequences; (5) generating a signal from each subensemble; (6) homogenously mixing the generated signals; and (7) simultaneously acquiring a complete multidimensional nuclear magnetic resonance data set for each preselected short time interval.
  • the application of multidimensional NMR to hyperpolarized spin states is described by B. M. Goodson, J. Magn. Reson. 155, 157 (2002) and P. J. Carson, C. R. Bowers, D. P. Weitekamp J. Am. Chem. Soc.
  • the single scan can be carried out by: (2) partitioning a predetermined sample of the on-going hyperpolarized spin system into a set of independent subensembles; (4) applying the single scan to the sample by exciting the set of subensembles by a time-incremented series of selective excitation sequences; (5) generating a signal from each subensemble; (6) homogenously mixing the generated signals; and (7) simultaneously acquiring a complete multidimensional nuclear magnetic resonance data set for each preselected short time interval.
  • the present invention has particular application to the characterization of analytes subject to flow through a NMR spectrometer, and thereby the coupling of multidimensional NMR with high-throughput chromatographic techniques.
  • a NMR spectrometer As described in H. H. Liu, C. Felten, Q. F. Xue, B. L. Zhang, P. Jedrzejewski, B. Karger, M. E. Lacey, R. Subramanian, D. L. Olson, A. G. Webb and J. V. Sweedler, Chem. Rev. 99, 3133 (1999) and K. Albert, On-Line Liquid Chromatography-NMR and Related Techniques.
  • This is accomplished by the present invention by the method for the realtime monitoring of one or more samples of a material undergoing a chromatographic technique comprising the steps of: (1) monitoring an on-going chromatographic technique in real time by repeatedly acquiring multidimensional nuclear magnetic resonance spectra within a single scan at preselected short time intervals; each single scan being carried out comprising the steps of the methods described herein previously in detail.
  • the single scan can be carried out by: (2) partitioning a predetermined sample of the on-going chromatographic technique into a set of independent subensembles; (3) applying the single scan to the sample by exciting the set of subensembles by a time-incremented series of selective excitation sequences; (4) generating a signal from each subensemble; (5) homogenously mixing the generated signals; and (6) simultaneously acquiring a complete multidimensional nuclear magnetic resonance data set for each preselected short time interval.
  • Combinatorial Chemistry is a novel approach to the synthesis of organic, inorganic and pharmacological molecules, whereby thousands of compounds are synthesized and tested in a variety of ways for chemical and/or biological activity. Combinatorial methods have provided much of the impetus for the ongoing revolution currently undergoing in Proteomics and Metabonomics. The enormous number of compounds that this approach requires be tested only allows high-throughput analytical techniques to participate in these tests and characterizations.
  • the invention described in this patent will now allow the incorporation of ultrafast multidimensional NMR methods to this array of high- throughput techniques, thereby providing a new route to the discovery of new catalysts, new pharmaceuticals, pharmaceutically-active peptides and nucleic acids, etc.
  • This is accomplished by the present invention by the method for the rapid and real-time monitoring of a combinatory chemistry involving a plurality of samples of a number of different materials comprising the steps of: (1) rapidly monitoring an ongoing combinatorial chemistry technique involving a plurality of samples in real time by repeatedly successively acquiring multidimensional nuclear magnetic resonance spectra within a single scan of successive samples; each single scan being carried out with respect to a sample and comprising the steps of the methods described herein previously in detail.
  • the single scan can be carried out by: (2) partitioning each successive sample of the on-going combinatorial chemistry technique into a set of independent subensembles; (3) applying the single scan to the sample by exciting the set of subensembles by a time-incremented series of selective excitation sequences; (4) generating a signal from each subensemble; (5) homogenously mixing the generated signals; and (6) simultaneously acquiring a complete multidimensional nuclear magnetic resonance data set for each successive sample.
  • This is accomplished by the present invention by the method for controlling a multidimensional NMR quantum computer with respect to a sample of a material comprising the steps of: (1) rapidly monitoring a multidimensional NMR quantum computer with respect to a sample in real time by acquiring multidimensional nuclear magnetic resonance spectra within a single scan of the sample, and using the spectra for controlling the operation of the multidimensional NMR quantum computer.
  • the single scan is carried out with respect to the sample and comprises the steps of the methods described herein previously in detail.
  • the single scan can be carried out by: (2) partitioning the sample into a set of independent subensembles; (3) applying the single scan to the sample by exciting the set of subensembles by a time-incremented series of selective excitation sequences; (4) generating a signal from each subensemble; (5) homogenously mixing the generated signals; and (6) simultaneously acquiring a complete multidimensional nuclear magnetic resonance data set for the respective sample.
  • the present invention bypasses such limitation, providing a new way to obtain the structure of macromolecules in their native states.
  • This is accomplished present invention by the method for the structural elucidations of a large molecule with respect to a sample of a molecule comprising the steps of: (1) rapidly monitoring a large molecule with respect to a sample in real time by acquiring multidimensional nuclear magnetic resonance spectra within a single scan of the sample, and using the spectra for elucidating the large molecule. I t may be necessary to repeat the single scan a multiple of times to obtain a set of spectra. The single scan is carried out with respect to the sample and comprises the steps of the methods described herein previously in detail.
  • the single scan can be carried out by: (2) partitioning the sample into a set of independent subensembles; (3) applying the single scan to the sample by exciting the set of subensembles by a time-incremented series of selective excitation sequences; (4) generating a signal from each subensemble; (5) homogenously mixing the generated signals; and (6) simultaneously acquiring a complete multidimensional nuclear magnetic resonance data set for the respective sample.
  • a further subordinate method of the present invention concerns ultrafast multidimensional NMR that can be applied regarding in vivo spectroscopy and the following of fast metabolic processes, as described in M. S. Cohen, Ed., Physiological NMR Spectroscopy: From Isolated Cells to Man, Ann. N. Y. Acad. Sci. (vol. 508, New York, 1987), both in basic research as well as in clinical diagnosis applications, such as described in M. A. Thomas, et al., Magn. Reson. Med. 46, 58 (2001).
  • multidimensional NMR spectroscopy on animals and/or humans is currently hampered by the long times that subjects need to reside within the NMR magnet for the completion of the experiments, a demand which should be greatly eased by the practice of this novel invention.
  • This is accomplished by present invention by the method for in vivo spectroscopy with respect to a sample comprising the steps of: (1 ) rapidly monitoring the sample in real time by acquiring multidimensional nuclear magnetic resonance spectra within a single scan of the sample, and using the spectra for evaluating the sample. It may be necessary to repeat the single scan a multiple of times to obtain a set of spectra.
  • the single scan is carried out with respect to the sample -and comprises the steps of the methods described herein previously in detail.
  • the single scan can be carried out by: (2) partitioning the sample into a set of independent subensembles; (3) applying the single scan to the sample by exciting the set of subensembles by a time-incremented series of selective excitation sequences; (4) generating a signal from each subensemble; (5) homogenously mixing the generated signals; and (6) simultaneously acquiring a complete multidimensional nuclear magnetic resonance data set for the respective sample.
  • the method for magnetic resonance imaging with respect to a sample comprising the steps of: (1) rapidly monitoring the sample in real time by acquiring multidimensional nuclear magnetic resonance spectra within a single scan of the sample at a preselected short time interval during the performance of an MRI protocol, and using the spectra for evaluating the sample or creating an image of the sample. It may be necessary to repeat the single scan a multiple of times to obtain a set of spectra and to obtain a plurality of images.
  • the single scan is carried out with respect to the sample and comprises the steps of the methods described herein previously in detail.
  • the single scan can be carried out by: (2) partitioning the sample into a set of independent subensembles; (3) applying the single scan to the sample by exciting the set of subensembles by a time-incremented series of selective excitation sequences; (4) generating a signal from each subensemble; (5) homogenously mixing the generated signals; and (6) simultaneously acquiring a complete multidimensional nuclear magnetic resonance data set for the respective sample.
  • the method for non-MNR multidimensional spectroscopy with respect to a system comprising the steps of: (1) rapidly monitoring the system in real time by acquiring spectra based on the response of the system as a function of an incremented time variable within a single scan of the system at a preselected short time interval during the functioning of the system, and using the spectra for evaluating the system or creating an image of the system. It may be necessary to repeat the single scan a multiple of times to obtain a set of spectra and to obtain a plurality of images.
  • the single scan is carried out with respect to the system and comprises the steps of the methods described herein previously in detail.
  • the single scan can be carried out by: (2) partitioning the system or its region of interest into a set of independent subensembles; (3) applying the single scan to the system or ROI by exciting the set of subensembles by a time- incremented series of selective excitation sequences; (4) generating a signal from each subensemble; (5) homogenously mixing the generated signals; and (6) simultaneously acquiring a complete multidimensional data set for the system.
  • the apparatus consists of a magnet 100 that generates a high-quality, high-intensity magnetic field that is uniform within the volume of a sample 106 undergoing test or monitoring.
  • the magnet is made of a superconducting wire, and includes an ancillary shim coil system for achieving a part-per-million homogeneity over the desired volume.
  • the magnet 100 can be made from other materials as is known in the art. Included within this embodiment are the coils 102 for generating the magnetic field gradients required by the invention.
  • the magnetic field strength is normally stabilized with the aid of an additional locking circuitry.
  • a probehead unit 104 in the magnet 100 is positioned the sample 106 and RF coils 108.
  • the probehead unit 104 (“probe") contains the sample 106 to be studied, as well as ancillary electronic equipment, including the coils 102 needed for generating the field gradients required by the invention, the electronics associated with an efficient RF irradiation of the spins, and the circuitry for an efficient detection of the spins' signal. Numerous such gradient and RF circuits are present in the single probe; the former for accounting for the three spatial directions, the latter for the simultaneous irradiation of multiple nuclear species ( 1 H, 2 H, 13 C, etc.).
  • the gradient wave form generator and driver unit 110 is comprised of a digital gradient waveform generator and a gradient driver that translates these digital signals into low-level analog currents, which are fed to gradient amplifiers X, Y, Z via lines 140 where these low-level signals are translated into intense high gradient driving currents that are supplied via lines 142 to the gradient coils 102 surrounding the sample 106.
  • Three such units are independently present, driving orthogonal x, y and z geometries (for different spatial directions). Additional geometries (additional spatial directions) can be added for 4D and higher dimension NMR (e.g. 5 th , 6 th ' etc.), each requiring its own gradient coils 102 for driving the additional orthogonal geometries (spatial directions).
  • RF Generation and Irradiation Unit 112 is comprised of an RF unit having a low-level synthesizer generating the basic low power RF signal used to irradiate a spin, an amplitude- and phase-control stage capable of creating pulses of different frequencies and shapes. Unit 112 is coupled via lines 136 to and feeds high-power amplifiers 114 that translate these low-level signals into the intense pulses that are fed via lines 138 to common lines 139 into the RF coils 108 in the probe 104 for the actual irradiation. Common lines 139 serve as multiple RF Channels In/Signals Out.
  • Unit 112 also provides a reference RF for the subsequent demodulation of the spins' signal from the radio (MHz) to the audio (kHz) range via line 134 to RF Signal Detection/Demodulation Unit 124.
  • Several such units are usually present, one per spin species to be irradiated during a particular sequence ( 1 H, 13 C, 15 N, 2 H, etc.).
  • a Signal Detection Unit receives the RF signal from spins via multiple RF channels In/Signals Out line 139 and coupled line 144.
  • the Unit is comprised of an RF signal preamplifier/amplifier 120 to effect the requisite preamplification, and then, amplification.
  • Preamplifier/amplifier 120 is coupled, in turn, to an RF Signal Detection/Demodulation unit 124 including the functions of demodulation and detection, which in turn is coupled to an Analog-to-Digital Data Acquisition Unit 126 that contains the digitization components, capable of transforming the voltage originally generated by the spins following their irradiation into a string of complex numbers (the Free Induction Decay or FID).
  • a Computer and Display 130 is coupled to Fast Pulse Programmers 132, which receive instructions from the computer 130, via bus 150, as indicated in Figure 13. These components 130 and 132 are responsible for interfacing to the user, and then creating the desired sequence of commands that all remaining units in the apparatus will carry out during the course of the operation of the apparatus or the experiment.
  • the computer 130 also provides instructions via bus 152 to the RF generation unit 112 and to the Gradient Wave Form Generator Driver Unit 110.
  • user's commands, input via a standard I/O 154, such as a keyboard or other such input device are translated by the computer 130 into strings of binary digits and logical timing signals, that are in turn executed by the various units.
  • the computer 130 containing adequate memory is also usually the final depository of the digitized FID, where its data is processed into an NMR spectrum according to the algorithms and other information set forth above and display takes place.
  • the Fast Pulse Programmers 132 are connected by buses 160 and 162 to provide fast timing control to the RF Signal Detection/Demodulation Unit 124, the RF generation unit 112 and the Gradient Wave Form Generator and Driver Unit 110.
  • step S1 is to let NMR magnetization generate to obtain relaxation.
  • step S2 an RF pulse sequence derived from RF generation unit 112 is applied to the sample 106 in combination with a field gradient obtained from the Gradient Wave Form Generator and Driver Unit 110.
  • step S3 in this fashion a spatially-incremented series of spin states is generated in sample 106, each spin state corresponding to different evolution times.
  • step S3 can be repeated, if needed, once per indirect dimension as desired, as indicated by the loop back shown in the flow chart from step S3 to step S2. Then in step S4, if needed, a final homogenous RF pulse sequence is applied capable of generating an observable signal.
  • step S5 the signals are collected within a single continuous scan, while in the presence of oscillating field gradients that reveal the spins original positions (one per indirect k dimension), and of a final acquisition time f / v-
  • step S6 the resulting single-scan signal is subjected to a suitable rearrangement along its multiple k axes, and to Fourier analysis as a function of the final acquisition time fw-
  • the present invention i.e., system or apparatus described in detail in this description of specific embodiments and as generally depicted in Figure 13 or any part thereof
  • the computer system of the invention represents any single or multi-processor computer, and in conjunction therewith, single-threaded and multi-threaded applications can be used. Unified or distributed memory systems can be used.
  • system and method of the present invention is implemented in a multi-platform (platform independent) programming language such as Java, programming language/structured query language (PL/SQL), hyper-text mark-up language (HTML), practical extraction report language (PERL), Flash programming language, common gateway interface/structured query language (CGI/SQL) or the like and can be implemented in any programming language and browser, developed now or in the future, as would be apparent to a person skilled in the relevant art(s) given this description.
  • a multi-platform (platform independent) programming language such as Java, programming language/structured query language (PL/SQL), hyper-text mark-up language (HTML), practical extraction report language (PERL), Flash programming language, common gateway interface/structured query language (CGI/SQL) or the like and can be implemented in any programming language and browser, developed now or in the future, as would be apparent to a person skilled in the relevant art(s) given this description.
  • system and method of the present invention may be implemented using a high-level programming language (e.g., C++) and applications written for the Microsoft Windows NT or SUN OS environments. It will be apparent to persons skilled in the relevant art(s) how to implement the invention in alternative embodiments from the teachings herein.
  • a high-level programming language e.g., C++
  • applications written for the Microsoft Windows NT or SUN OS environments e.g., C++
  • the Computer system of the invention includes one or more processors and can execute software implementing the routines described above, such as shown in Figure 14.
  • Various software embodiments are described in terms of this exemplary computer system. After reading this description, it will become apparent to a person skilled in the relevant art how to implement the invention using other computer systems and/or computer architectures.
  • the Computer system can include a display interface that forwards graphics, text, and other data from the communication infrastructure (or from a frame buffer not shown) for display on the display unit included as part of the system.
  • the Computer system also includes a main memory, preferably random access memory (RAM), and can also include a secondary memory.
  • the secondary memory can include, for example, a hard disk drive and/or a removable storage drive, representing a floppy disk drive, a magnetic tape drive, an optical disk drive, etc.
  • the removable storage drive can read from and/or write to a removable storage unit in a well- known manner.
  • a secondary memory may include other similar means for allowing computer programs or other instructions to be loaded into computer system.
  • Such means can include, for example, a removable storage unit and an interface. Examples can include a program cartridge and cartridge interface (such as that found in video game console devices), a removable memory chip (such as an EPROM, or PROM) and associated socket, and other removable storage units and interfaces that allow software and data to be transferred from the removable storage unit to computer system.
  • the Computer system can also include a communications interface that allows software and data to be transferred between computer system and external devices via a communications path.
  • communications interface can include a modem, a network interface (such as Ethernet card), a communications port, interfaces described above, etc.
  • Software and data transferred via a communications interface are in the form of signals that can be electronic, electromagnetic, optical or other signals capable of being received by communications interface, via a communications path.
  • a communications interface provides a means by which computer system can interface to a network such as the Internet.
  • the present invention can be implemented using software running (that is, executing) in an environment similar to that described above with respect to Figure 14.
  • computer program product is used to generally refer to removable storage unit, a hard disk installed in hard disk drive, or a carrier wave carrying software over a communication path (wireless link or cable) to a communication interface.
  • a computer useable medium can include magnetic media, optical media, or other recordable media, or media that transmits a carrier wave or other signal.
  • Computer programs are stored in main memory and/or secondary memory. Computer programs can also be received via a communications interface. Such computer programs, when executed, enable the computer system to perform the features of the present invention as discussed herein. In particular, the computer programs, when executed, enable the processor to perform features of the present invention. Accordingly, such computer programs represent controllers of the computer system.
  • the present invention can be implemented as control logic in software, firmware, hardware or any combination thereof.
  • the software may be stored in a computer program product and loaded into computer system using a removable storage drive, hard disk drive, or interface.
  • the computer program product may be downloaded to computer system over a communications path.
  • the control logic when executed by the one or more processors, causes the processor(s) to perform functions of the invention as described herein.
  • the invention is implemented primarily in firmware and/or hardware using, for example, hardware components such as application specific integrated circuits (ASICs).
  • ASICs application specific integrated circuits

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Abstract

L'invention concerne un procédé et un appareil de traitement d'un échantillon aux fins d'acquisition d'un spectre multidimensionnel par un balayage unique divisant un échantillon en un ensemble de sous-ensembles indépendants possédant différentes fréquences de résonance. On met en oeuvre une irradiation polychromatique de l'échantillon dans laquelle les sous-ensembles variés sont sélectivement manipulés par une série d'excitations à incrémentation temporelle ou de séquences de refocalisation. Puis, on applique une séquence homogène capable de générer un signal de spectre observable à partir de chacun des sous-ensembles avec un suivi simultané des signaux observables provenant des sous-ensembles variés d'une façon résolue. Les signaux observables acquis de cette façon sont traités dans un ensemble complet de données spectrales multidimensionnelles.
PCT/US2003/021314 2002-07-26 2003-07-07 Procede et appareil d'acquisition de spectre multidimensionnel par un balayage unique WO2004011899A2 (fr)

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EP03771578.6A EP1529227B1 (fr) 2002-07-26 2003-07-07 Procede et appareil d'acquisition de spectre multidimensionnel par un balayage unique
AU2003247923A AU2003247923A1 (en) 2002-07-26 2003-07-07 Method and apparatus for acquiring multidimensional sprectra within a single scan
IL16641703A IL166417A0 (en) 2002-07-26 2003-07-07 Method and apparatus for acquiring multidimensional spectra within a single scan
US10/728,069 US6873153B2 (en) 2003-07-07 2003-12-04 Method and apparatus for acquiring multidimensional spectra and improved unidimensional spectra within a single scan
US11/056,131 US7271588B2 (en) 2003-07-07 2005-02-10 Method and apparatus for acquiring multidimensional spectra and improved unidimensional spectra within a single scan
IL220203A IL220203A (en) 2002-07-26 2012-06-06 A method and facility for obtaining multi-dimensional spectra in a single scan

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004090563A1 (fr) * 2003-04-14 2004-10-21 Amersham Health R & D Ab Spectroscopie rmn multidimensionnelle d'un echantillon hyperpolarise
EP1555538A1 (fr) * 2004-01-15 2005-07-20 Bruker BioSpin MRI GmbH Procédé de spectroscopie rmn rapide multidimensionnelle
EP1694280A2 (fr) * 2003-12-04 2006-08-30 YEDA RESEARCH AND DEVELOPMENT CO., Ltd. Procede et appareil d'acquisition de spectres multidimensionnels et unidimensionnels ameliores en un seul balayage
US7746071B2 (en) 2005-04-08 2010-06-29 Bruker Biospin Gmbh Method for the acquisition of data relating to multi-dimensional NMR spectra by means of frequency-dependent convolution
US7944206B2 (en) 2005-12-21 2011-05-17 Yeda Research And Development Co. Ltd. Method and apparatus for acquiring high resolution spectral data or high definition images in inhomogeneous environments
WO2014203253A1 (fr) 2013-06-19 2014-12-24 Yeda Research And Development Co. Ltd. Procédés pour sélectivité spatiale et spectrale dans l'imagerie à résonance magnétique et la spectroscopie
US10794980B2 (en) 2015-08-04 2020-10-06 Yeda Research And Development Co. Ltd. Cross-term spatiotemporal encoding for magnetic resonance imaging

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5064683A (en) * 1990-10-29 1991-11-12 Motorola, Inc. Method for polish planarizing a semiconductor substrate by using a boron nitride polish stop
US6037772A (en) * 1998-01-06 2000-03-14 Arch Development Corp. Fast spectroscopic imaging system
US6184683B1 (en) * 1998-07-29 2001-02-06 Bruker Analytik Gmbh Method to improve resolution of two-dimensional heteronuclear correlation spectra in solid-state NMR
US6504368B2 (en) * 2000-04-18 2003-01-07 Hoffmann-La Roche Inc. Spectroscopic measurement method using NMR

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4629988A (en) * 1984-07-02 1986-12-16 General Electric Company Method of imaging by depth-resolved surface coil spectroscopy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5064683A (en) * 1990-10-29 1991-11-12 Motorola, Inc. Method for polish planarizing a semiconductor substrate by using a boron nitride polish stop
US6037772A (en) * 1998-01-06 2000-03-14 Arch Development Corp. Fast spectroscopic imaging system
US6184683B1 (en) * 1998-07-29 2001-02-06 Bruker Analytik Gmbh Method to improve resolution of two-dimensional heteronuclear correlation spectra in solid-state NMR
US6504368B2 (en) * 2000-04-18 2003-01-07 Hoffmann-La Roche Inc. Spectroscopic measurement method using NMR

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1529227A2 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004090563A1 (fr) * 2003-04-14 2004-10-21 Amersham Health R & D Ab Spectroscopie rmn multidimensionnelle d'un echantillon hyperpolarise
US7550970B2 (en) 2003-04-14 2009-06-23 Ge Healthcare As Multidimensional NMR spectroscopy of a hyperpolarized sample
EP1694280A2 (fr) * 2003-12-04 2006-08-30 YEDA RESEARCH AND DEVELOPMENT CO., Ltd. Procede et appareil d'acquisition de spectres multidimensionnels et unidimensionnels ameliores en un seul balayage
EP1694280A4 (fr) * 2003-12-04 2009-06-24 Yeda Res & Dev Procede et appareil d'acquisition de spectres multidimensionnels et unidimensionnels ameliores en un seul balayage
EP2492703A1 (fr) * 2003-12-04 2012-08-29 Yeda Research and Development Co. Ltd. Procédé et appareil d'acquisition de spectre multidimensionnel par un balayage unique
EP1555538A1 (fr) * 2004-01-15 2005-07-20 Bruker BioSpin MRI GmbH Procédé de spectroscopie rmn rapide multidimensionnelle
US7746071B2 (en) 2005-04-08 2010-06-29 Bruker Biospin Gmbh Method for the acquisition of data relating to multi-dimensional NMR spectra by means of frequency-dependent convolution
US7944206B2 (en) 2005-12-21 2011-05-17 Yeda Research And Development Co. Ltd. Method and apparatus for acquiring high resolution spectral data or high definition images in inhomogeneous environments
WO2014203253A1 (fr) 2013-06-19 2014-12-24 Yeda Research And Development Co. Ltd. Procédés pour sélectivité spatiale et spectrale dans l'imagerie à résonance magnétique et la spectroscopie
US10794980B2 (en) 2015-08-04 2020-10-06 Yeda Research And Development Co. Ltd. Cross-term spatiotemporal encoding for magnetic resonance imaging

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IL220203A0 (en) 2012-07-31
WO2004011899A3 (fr) 2004-07-15
IL220203A (en) 2014-05-28
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EP1529227A2 (fr) 2005-05-11

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